Several drugs have been withdrawn from the
U.S.
market or have received black box warnings due to their potential to cause QT
interval prolongation that leads to fatal ventricular arrhythmias and sudden
cardiac death.1,2 Predicting the risks involved with most of these
drugs is difficult, since they are often structurally and pharmacologically
unrelated. However, a patient's risk of a fatal ventricular arrhythmia may be
reduced with the pharmacist's awareness of nonpharmacologic risk factors,
drugs known to cause QT prolongation, and specific drug interactions.

QT Interval
The QT interval is the length of time required for the heart to repolarize
following the onset of depolarization. Ventricular depolarization, expressed
as the QRS complex on an electrocardiogram (ECG), is the rapid movement of
ions (sodium, potassium, and calcium) across the cellular membrane, creating
electrical impulses that lead to ventricular contraction. When the outflow of
potassium from the myocardium exceeds the inflow of sodium and calcium,
repolarization occurs and is expressed as the T wave on the ECG.

The QT interval is measured on an ECG from the
start of the QRS complex to the end of the T wave.1,3 If the ion
channels of the myocardium malfunction, most commonly the delayed potassium
rectifier channels (IKr), an excess sodium influx or a decreased potassium
efflux may result. This surplus of positively charged ions leads to an
extended repolarization phase, thus resulting in a prolonged QT interval,
causing arrhythmias such as torsades de pointes (TdP), a potentially
life-threatening ventricular arrhythmia.1,3

Heart rate can affect the time for repolarization.
Rapid heart rate can lead to a shortened QT interval. To correct for this,
the QT interval is often expressed as the heart rate-corrected QT interval
(QTc).1,3 The QTc can be calculated using the Bazett formula, which
corrects for heart rate by dividing the QT interval by the square root of the
difference between the Rs of two QRS complexes (QTc = QT/RR).1-3

The QTc is considered prolonged if the values are
greater than 450 milliseconds in males and greater than 470 milliseconds in
females.3 The risk of cardiac events correlates with the extent of
QT prolongation. However, no QTc value has been established for cardiac
arrhythmia. The most common ventricular arrhythmias such as TdP have been
associated with a QTc greater than 500 milliseconds.2,3

Nonpharmacologic Risk Factors
Several factors influence the risk of drug-induced QT prolongation (Table 1
). Female gender has been documented in many studies as a risk factor, with
females having baseline QTc intervals that are generally 20 milliseconds
greater than that of males.2,3 Cardiac conditions such as
bradycardia and heart failure have also been indicated as nonpharmacologic
risk factors for drug-induced QT prolongation and TdP. Slow heart rate
prolongs the repolarization phase, making an individual vulnerable to
drug-induced prolongation of the QT interval. Heart failure has been
associated with extended action potentials by blocked IKr channels, leading to
an increased risk of drug-induced arrhythmias. Electrolyte abnormalities
(e.g., hypokalemia, hypocalcemia, and hypomagnesemia) may elevate the risk of
QT prolongation. Genetic mutations within the cardiac sodium channels can also
raise the risk of QT prolongation and TdP. Although these nonpharmacologic
risk factors, when combined with certain drugs, increase patients' risk for QT
prolongation, it is difficult to predict the rate at which specific drugs may
cause QT prolongation or TdP.

Drugs Commonly Associated with QT Prolongation
Antiarrhythmic agents were the first drugs associated with QT prolongation and
ventricular arrhythmias. Recently, there has been an increased incidence of
arrhythmia caused by noncardiac medications, generating significant concern
and, in some cases, withdrawal of these drugs from the
U.S.
market (Table 2).

Antiarrhythmic Agents:
Class I antiarrhythmic agents (e.g., quinidine, disopyramide, and
procainamide) have frequently been linked to inducing arrhythmia, including
TdP.3,4 Reports have estimated that quinidine can cause TdP in 1%
to 8% of patients, even at lower doses.4 Sotalol and amiodarone,
class III antiarrhythmics, are known to prolong the QT interval by blocking
the IKr. However, the risk of TdP with amiodarone is low when compared with
sotalol.3,4 Higher drug concentrations of sotalol can lead to QTc
intervals that are prolonged by approximately 10 to 40 milliseconds, thereby
increasing the incidence of TdP. With the exception of quinidine, the degree
of QT prolongation linked to the antiarrhythmics depends on the serum drug
level.5

Antimicrobial Agents:Fluoroquinolones, macrolides, and
antifungal agents have been associated with prolonged QT interval and TdP.
3 Quinolones are widely used antibiotics frequently prescribed for the
treatment of respiratory and urinary tract infections. Ciprofloxacin,
levofloxacin, gatifloxacin, and moxifloxacin are the most commonly prescribed
fluoroquinolones in the United States.6 Sparfloxacin--the only
fluoroquinolone to exhibit activity similar to class III antiarrhythmics--was
found to be the most likely of these agents to cause a prolonged QTc interval,
leading to its withdrawal from the market.7 Grepafloxacin (not
marketed in the U.S.) has also been shown to increase the QTc interval,
although not as significantly as sparfloxacin.7 Seventeen case
reports of levofloxacin-induced TdP have been published in the literature as
of 2005.

Macrolides, specifically erythromycin, exhibit
electrophysiologic effects similar to those of the class III antiarrhythmics
(amiodarone, sotalol, ibutilide, and dofetilide). Macrolides can prolong
myocardial action potential by dispersing electrical activity over the
ventricular wall, leading to a prolonged QT interval or TdP. Erythromycin is
also an inhibitor of CYP3A4, which poses the danger of significant
pharmacokinetic interactions with numerous drugs, most significantly cisapride.
1,4

Antifungals, such as ketoconazole and
itraconazole, may have an effect on potassium channels and result in a
prolonged QT interval. Antifungals are also potent inhibitors of CYP3A4.
Consequently, when medications metabolized by the 3A4 isoenzyme are
coadministered with antifungals, the risk for QT prolongation increases
significantly.1-4

Antipsychotic Agents:In the past, antipsychotic agents have
been linked to an increased risk of sudden death. It has been recently
suggested that this risk may be associated with QT prolongation; however, this
is difficult to determine without ECG results. The structural difference of
the antipsychotics makes it difficult to assess the effects these agents may
have on QT intervals.8 Although the exact mechanism by which
antipsychotics lead to QT prolongation is unclear, they appear to exert their
effects by blocking the IKr potassium channels, leading to delayed
repolarization. Interference with sodium and calcium channels is another
potential mechanism.8-10 Regardless of the mechanism, QT
prolongation associated with antipsychotics appears to be related to the dose
and plasma concentration of the drug.

Thioridazine, a phenothiazine antipsychotic that
causes significant blockade of the IKr channels, has been associated with QTc
prolongation and TdP that has resulted in sudden death. The manufacturer of
thioridazine now recommends that its use be restricted to patients who have
not responded to other antipsychotics or patients who are experiencing
intolerable side effects with other agents.9

Cases of QT prolongation, TdP, and death have also
been associated with the use of haloperidol at therapeutic doses. However, the
risk of adverse cardiac effects appears to be far lower with haloperidol when
compared with thioridazine. Unlike thioridazine, haloperidol is still widely
used. High doses of droperidol have also been associated with QT prolongation;
droperidol now has a black box warning indicating this risk.9

Atypical antipsychotic agents have also been
associated with QT prolongation. Yet, the risk of TdP appears to be lower than
that of thioridazine. The risk of QT prolongation seems to be greatest with
ziprasidone compared with other atypical agents. A black box warning was added
to the ziprasidone label, citing the risk of ventricular arrhythmias, but the
risk of TdP or sudden death is rare. Other atypical antipsychotic agents--such
as cloza­ pine, quetiapine, risperidone, and olanzapine--may also cause QT
prolongation, which is typically dose related.8-10

Antihistamines:Nonsedating antihistamines were
considered potential causes of QT prolongation. Terfenadine and astemizole
were found to have proarrhythmic effects, which led to their withdrawal from
the market in 1998 and 1999, respectively.11 Although terfenadine
was associated with an increased risk of TdP, the active metabolite
fexofenadine was not and is now on the market.3,4 Drug interactions
affecting the cytochrome P450 system and potential inhibition of the IKr
channels are most likely the cause of QT prolongation. Newer nonsedating
antihistamines (e.g., loratadine, fexofenadine, and cetirizine) have not been
linked to this risk.

Antidepressants:Tricyclic antidepressants (TCAs) and
selective serotonin reuptake inhibitors (SSRIs) have also been associated with
QT prolongation and TdP. TCAs act on both sodium and IKr channels, which can
potentially lead to electrophysiologic changes, such as widening of the QRS
complex and QT interval prolongation. When used in combination with drugs that
inhibit metabolism, or if overdose occurs, the risk is increased.4,12
Although there have been several case reports associating the risk of QT
prolongation and SSRIs, the documentation is limited and appears to occur as a
result of pharmacokinetic interaction.

Drug Interactions
Both pharmacokinetic and pharmacodynamic drug interactions can significantly
increase the risk of QT prolongation. Pharmacists may help reduce the risk of
serious ventricular arrhythmias by screening for potential interactions.

Pharmacokinetic:The majority of drugs that potentially
prolong the QT interval are hepatically metabolized by the cytochrome
isoenzymes CYP3A4, 1A2, and 2D6, with CYP3A4 responsible for the metabolism of
approximately 50% of all drugs.13 Most drugs that prolong the QT
interval work in a concentration-dependent manner. Furthermore, it is
intuitive that inhibiting the metabolism of these commonly associated
medications can significantly increase the risk for QTc prolongation or TdP.
The drug interactions listed in Table 3 are likely to increase a
patient's risk for QTc prolongation, further leading to TdP. For example,
prior to terfenadine's withdrawal from the market, the QTc prolongation
associated with this drug was estimated to be about 8 to 18 milliseconds. When
studied along with the administration of ketoconazole, a 3A4 inhibitor, the
QTc interval increased by 82 milliseconds.9 Renal impairment may
also increase a patient's risk for QT interval prolongation by the
accumulation of drug.

Pharmacodynamic:Pharmacodynamic interactions may also
lead to QT prolongation. These interactions occur as a result of synergistic
or antagonistic pharmacologic properties. Several drugs are known to cause QT
prolongation (see Table 2 ); the potential risk increases when such
drugs are used in combination.

Risks Versus Benefits
Risks and benefits should be assessed when selecting medications known to
prolong QT interval. Of course, the benefits of certain medications may far
outweigh the risks associated with their use. For example, arsenic trioxide,
although known to induce arrhythmia, may be necessary for the treatment of
acute promyelocytic leukemia. However, it is important to note that generally,
in other cases, a safer alternative may be available.

The incidence of QT prolongation and TdP is well
documented with the antiarrhythmic agents. Although they are beneficial for
the acute termination of an arrhythmia, there has been little documentation
supporting their use for chronic management of arrhythmias.1 Thus,
the risk of long-term management with antiarrhythmics may outweigh the
potential benefits.

As previously mentioned, it is important to assess
the nonpharmacologic risk factors (Table 1) when selecting a medication
that has been associated with QT prolongation. Close monitoring is
particularly necessary when choosing to use QT-prolonging drugs within this
population of patients at risk. Patients should be counseled about the
potential risks associated with these medications and informed of the symptoms
of arrhythmia. Patients should seek medical attention if symptoms such as
lightheadedness, dizziness, palpitations, shortness of breath, or syncope
occur.

Conclusion
Although QT prolongation has been linked to the use of certain drugs, it
remains difficult to predict the relative risk associated with their
administration. Pharmacists can make recommendations to clinicians to help
promote safer prescribing practices when selecting QT-prolonging drugs. Drugs
that have QT-prolonging effects should not exceed recommended dosing range, as
drug-induced arrhythmia is often a result of high drug concentrations. In
addition, these medications should be prescribed with caution in patients who
have underlying risk factors, such as cardiac disorders. Screening for
potential drug interactions and electrolyte abnormalities may also help lead
to safer therapies, potentially preventing the development of ventricular
arrhythmias.3